3-oximes of 19-nortestosterone esters

ABSTRACT

3-OXIMES OR 17-A-ETHYLNYL 19-NORTESTOSTERONE ESTERS HAVE POST-COITAL ACTIVITY FOR THE SUPPRESSION OF REPRODUCTION.

United States Patent 3,780,073 S-OXIMES OF 19-NORTESTOSTERONE ESTERSArvin P. Shroif, Piscataway, N.J., assignor to Ortho PharmaceuticalCorporation No Drawing. Continuation-impart of applications Ser. No.843,201, July 18, 1969, now Patent No. 3,629,415, and Ser. No. 193,174,Oct. 27, 1971, said application Ser. No. 843,201 being a division ofapplication Ser. No. 635,308, Apr. 20, 1967, now Patent No. 3,532,689,which is a continuation-impart of applications Ser. No. 502,384, Oct.22, 1965, now abandoned, and Ser. No. 563,081, July 6, 1966, now PatentNo. 3,437,674. This application Nov. 15, 1971, Ser. No. 198,992

Int. Cl. C07c 169/08 US. Cl. 260-3975 8 Claims ABSTRACT OF THEDISCLOSURE 3-oximes of 17-a-ethynyl l9-nortestosterone esters havepost-coital activity for the suppression of reproduction.

This is a continuation-in-part of application Ser. No. 193,174, filedOct. 27, 1971, and a continuation-in-part of application Ser. No.843,201 filed July 18, 1969, now US. Pat. No. 3,629,415 which was inturn a division of application Ser. No. 635,308 filed Apr. 20, 1967, nowPat. No. 3,532,689 which was in turn a continuation-inpart ofapplication Ser. No. 502,384 filed Oct. 22, 1965, now abandoned, andSer. No. 563,081 filed July 6, 1966 now Pat. No. 3,437,674.

The novel compounds of the present invention are represented by theformula:

HON

wherein R is alkanoyl of from 2 to 10 carbon atoms such as acetyl,propionyl, butyryl, pentanoyl, octanoyl, and

the like, and R is methyl or ethyl. The preferred compounds of theinvention are those wherein R has more than carbon atoms, such ascaproyl, nonanoyl and decanoyl and R is methyl. Alternatively, preferredcompounds include those wherein R is ethyl and R is acetyl.

The compounds of the invention possess valuable pharmacologic activityas antilittering agents, and more particularly, as agents for thesuppression of reproduction when given post-coitally. They have alsobeen found to be especially suitable as long acting compounds for thesuppression of reproduction when administered parenterally, especiallypre-coitally. They may be administered by any suitable parenteral means,intramuscular and sub-cutaneous being preferred.

The compounds of the invention are prepared by reacting a compound ofthe formula:

3,780,073. Patented Dec. 18, 1973 "ice wherein R and R have the meaninggiven above, with a hydroxylamine salt in the presence of a base such aspyridine, sodium hydroxide or sodium acetate to form the corresponding3-oxime.

Typical starting materials for the reaction are17aethynyl-l9-nortestosterone, which is disclosed in US. Pat. No.2,774,777 and its esters. These compounds are known as ovulationsuppressing agents which are used precoitally.

The following examples illustrate the invention:

EXAMPLE I 17u-ethynyl-17p-acetoxy-19=norandrost-4-en-3-one oxime Asolution of 2.0 g. of 17u-ethyny1-1713-acetoxy-19-norandrost-4-en-3-one, 10 ml. of pyridine and 1.0 g. of hydroxylaminehydrochloride is heated on a steam bath for one-half hour. The mixtureis poured into a large amount of ice and water and the solid thusseparated is collected by filtration. It is recrystallized frommethanolwater to give 1.6 g. (78%) of 17a-ethyny1-17p-acetoxy-19-norandrost-4-en-3-one oxime, M.P. 229-230.

)\ max. 238 mp.

Calcd. for C H NO (percent): C, 74.33; H, 8.22; N,

3.94. Found (percent): C, 74.39; H, 8.21; N, 4.01.

EXAMPLE II 17fi-caprolyloxy-17u-ethynyl-19-norandrost-4-ene-3-one oximel7a-ethynyl-l9-norandrost-4-en-l7B-ol-3-one (1.0 g.) is heated with 10ml. of pyridine and 300 mg. of hydroxylamine hydrochloride on a steambath for two hours. The solution is poured over a large amount of waterand the precipitates thus formed are collected by filtration.Recrystallization from methanol gives17a-ethynyl-l9-norandrost-4-en-17B-ol-3-one oxime, M.P. 112-114".

Calcd. for C26H37NO'3 (percent): C, 75.87; H, 9.06; N, 3.40. Found(percent): C, 75.66; H, 9.21; N, 3.14.

EXAMPLE III 17p-propionyloxy-17-wethynyl-19-norandrost-4-en-3-one oximeFollowing the procedure of Example I, but starting with 175caproyloxy-17a-ethynyl-19-norandrost-4-en-3- one, there is obtained 17fi-caproyloxy-17a-ethynyl-l9-norandrost-4-en-one oxime, M.P. -76".

Calcd. for C H NO (percent): C, 74.76; H, 8.46; N,

3.79. Found (percent): C, 74.78; H, 8.65; N, 3.17.

EXAMPLE V 17fi3-decanoyloxy-17a-ethnyl-l9'-norandrost-4-en-3-one oximeFollowing the procedure of Example I, but starting with17B-decanoyloxy-17u-ethyny1-l9-norandrost-4-en-3- one, there is obtained17,8-decanoyloxy-17u-ethyny1-19- norandrost-4-en-3-one oxime, M.P.128-4295".

43 Calcd. for C ,,H NO (percent): C, 77.04; H, 9.70; N,

3.00. Found (percent): C, 77.12; H, 9.87; N, 3.27.

In like manner there are prepared:

17a-ethynyl-13p-ethyl-gon-4-en-17/8-ol-3-one oxime,17u-ethynyl-17p-caproyloxy-13p-ethyl-gon-4-en-3-one oxime, and17a-ethynyl-l7fl-decanoyloxy-13p-ethyl-gon-4-en-3-one oxime.

EXAMPLE VI N, 17B-diacetoxy-17a-ethynyl-19-norandrost-4-en-3-one oximeacetoxy-19-norandrost-4-en-3-one oxime in 5.0 ml. of pyridine is treatedwith 9.08 ml. of acetic anhydride and stirred at room temperature for 15minutes. The mixture is poured into a large amount of ice and water andneutralized with ammonium hydroxide. The solid portion is collected byfiltration, dried and recrystallized from hexane to giveN,l7,8-diacetoxy-17a-ethynyl-l9-norandrost- 4-en-3-one oxime, M.P.142-144" C.

Calcd. for C H N (percent): C, 72.51; H, 7.86; N,

3.52. Found (percent): C, 72.54; H, 8.01; N, 3.73.

EXAMPLE VII N-iso-butyry1oxy-17 ,B-acetoxy-17 a-ethyny1-19-norandrost-4-en-3-one oxime A solution containing 3.0 g. ofl7a-ethynyl-l7fl-acetoxy-l9-norandrost-4-en-3-one oxime in 10 ml. ofpyridine is treated with 10 ml. of isobutyric anhydride. The mixture isstirred at room temperature for minutes, and poured into a large amountof ice and water. The semisolid material is extracted with ethyl acetateand the organic layer is washed with water, dried over sodium sulfateand evaporated. The solid is recrystallized from hexane to giveN-isobutyryloxy-17/3-acetoxy-17u-ethynyl-19- norandrost-4-en-3-oneoxime, M.P. 150-151 C.

has? 244 my.

Calcd. for C H NO (percent): C, 73.38; H, 8.29; N,

3.29. Found (percent): C, 73.31; H, 8.31; N, 3.53.

EXAMPLE VIII N-propionyloxy-17fi-acetoxy-17a-ethynyl-l9-norandrost-4-en-3-one oxime Following the procedure of Example VI orVII, but using propionic anhydride as the esterifying agent, N-propionyloxy-l7B-acetoxy-17a-ethynyl 19 norandrost- 4-en-3-one oxime isrecrystallized from hexane, M.P. 152- 154 C.

maxv

Calcd. for C H NO (percent): C, 74.14; H, 8.67; N, 3.09. Found(percent): C, 74.03; H, 8.55; N, 3.33.

EXAMPLE X N-acetoxy-17fi-caproyloxy-l7a-ethyny1-19-norandrost-4-en-3-one oxime Following the procedure of Example VI, butstarting with 17B-caproyloxy-17oc-ethynyl-l9-norandrost 4 en- 3-oneoxime, there is obtained N-acetoxyl-l7/3-caproyloxy-17a-ethynyl- 19-norandrost-4-en-3-one oxime, M.P. -112".

Calcd. for 'C H NO (percent): C, 74.14; H, 8.69; N, 3.13. Found(percent): C, 74.10; H, 8.69; N, 3.13.

EXAMPLE XI N-( 2'-tetrahydropyranyloxy) -17B-acetoxy-l7a-ethynyl-19-norandrost-4-en-3-one oxime l7fl-acetoxy-17a-ethynyl-19-norandrost 4en- 3-one oxime (0.5 g.) is treated with 20.0 ml. of dry benzene, 0.2 g.of p-toluenesulfonic acid and 10 ml. of dihydropyran and is stirred atroom temperature for 0.5 hour. The mixture is treated with a largeamount of ice and water followed by extraction with ethyl acetate. Theorganic layer is dried over sodium sulfate and evaporated. Repeatedcrystallization from methylene chloride-hexane givesN-(2-tetrahydropyranyloxy) acetoxy- 17ozethynyl-19-n0randrost-4-en-3-oneoxime, M.P. 172-174".

Calcd. for C27H37NO4 (percent): C, 73.77; H, 8.48; N,

3.19. Found (percent): C, 74.08; H, 8.32; N, 3.45.

EXAMPLE XII DL-13fi-ethyl-17u-ethynyl-1713-acetoxy-gon- 4-en-3-one oximeA solution containing 4.5 g. ofDL-13/3-ethyl-17aethynyl-17fi-acetoxy-gon-4-en-3-one in 15 ml. ofpyridine and 2.0 g. of hydroxylamine hydrochloride is heated on a steambath for 45 minutes. It is cooled and poured into a large amount of iceand water. The solid material thus formed is collected by filtration andair dried. It is recrystallized from methylene chloride-alcohol mixtureto give 4.2 g. of DL-13 3-ethyl-17a-ethynyl-17B-acetoxy-gon- 4-en-3-oneoxime, M.P. 226-228.

Calcd. for C H NO (percent): C, 74.76; H, 8.46; N,

3.79. Found (percent): C, 74.84; H, 8.75; N, 3.90.

In like manner there are prepared:

N,17 3-diacetoxy-17a-ethynyl-13fi-ethyl-gon-4-en-3- one oxime,

N-iso-butyryloxy-17/8-acetoxy-17a-ethynyl-13fi-ethylgon-4-en-3-oneoxime,

N-propionyloxy-17fl-acetoxy-17a-ethynyl-13,8-ethylgon-4-en-3-one oxime,

N-caproyloxy-17/3-acetoxy-17a-ethyny1-13 fl-ethyl-gon- 4-en-3-one oxime,

N-acetoxy-17 B-caproyloxy-17a-ethynyl-13 3-ethyl-gon- 4-en-3-one oxime,and

N- 2'-tetrahydropyranyloxy) -17fi-acetoxy-17u-ethynyl-13p-ethyl-gon-4-en-3-one oxime.

The antilittering eflect of a compound is determined by the followingprocedure:

(1) The compound to be tested is administered in the diet or by gavagefor 7 days to both male and female rats, with the sexes segregated.

(2) Treatment is continued for 15 days during which the rats arepermitted to cohabit freely.

(3) The sexes are again segregated and are observed for 21 days with notreatment.

A control group is similarly treated except that the compound is notadministered.

The females are observed for pregnancies and the size of litters.

The minimum effective dose (MED) is the amount of the compound inmilligrams per kilogram of animal body weight per day (mg./kg./day),which completely suppresses the production of litters.

5 TABLE I Compound administered: MED mg./kg./day

17a-ethynyl-l7fi-acetoxy-19-norandrost 4 en- N,17B-diacetoXy-17a-ethynyl19 norandrost- 4-en-3-one oxime N-propionyloxy-l7/3-acetoXy 17aethynyl-l9- norandrost-4-en-3-one oximeN-isobutyryloxy-17fi-acetoxy-17u-ethynyl 19- norandrost-4-en-3-one oximeN-caproyloxy-lm-acetoxy 17cc ethynyl 19- norandrost-4-en-3-one oxime N(2'-tetrahydropyranyloxy) 17/3 acetoxy- 17a-ethyny1-l9-norandrost 4 en 3one oxime 17;3-caproyloxy17a-ethyny1 19 norandrost- 4-en-3-0ne oxime0.25 175 propionyloxy-17a-ethynyl-l9-norandrost- 4-en-3-one oxime 0.25l7ot-ethynyl-l9-nortestosterone 20.017a-ethynyl-17fl-acetoxy-19-nortestosterone 5.0

It will be observed from Table I above that17a-ethynyl-17B-acetoxy-19-norandrost-4-en-3-one oxime eliminates theproduction of litters in rats at a dose of 0.25 mg. per kilogram of bodyweight per day, while a daily dosage of 5.0 mg./kilogram of body weightof its precursor 17aethynyl-l7fi-acetoxy-19-nortestosterone is requiredto accomplish the total suppression of litters. It will also be observedthat 0.25 mg. per kilogram of body weight per day of17a-ethynyl-19-norandrost 4 en 17B-ol-3-one oxime totally suppresses ratlitters while 20.0 mg. per kilogram of body weight per day of itsprecursor 17aethynyl-19-nortestosterone is required to accomplish totalsuppression of rat litters. It will further be observed that 0.25mg./kg. of body weight/day of 17fi-caproyloxy and 17,8propionyloxy-lh-ethynyl 19 norandrost-4-en-3- one oxime compounds of theinvention are suflicient to accomplish total suppression of rat litters.

In order to determine the post-coital efiect of a compound, female ratsof the Wistai" strain are fed a compound by gavage on specific days ofgestation after sperm are observed in the vagina. The rats aresacrificed and the uteri are examined for implantation and resorbtionsites.

In the following table, day 0 is the day on which sperm is observed invaginal washings and the compound tested was 170:ethynyl-17fi-acetoxy-19-norandrost-4-en-3-one oxime.

TABLE II Day of administration Implantations Normal Resorbed Pregnanttotal Dose (mg/kg.)

a: as H a 0 H03 to m most eflective from between 36 to 60 hours afterfertili- I zation of the ovum.

Inorder to determine the long acting nature of the compounds of thisinvention, female rats are given a single dose sub-cutaneously of thecompound in sesame oil (10 mg./m1.) 7 days before permittingcohabitation. The compound can also be administered intramuscularly. Thesexes are then permitted to cohabit freely for the number of daysindicated in Table III below. They are then segregated for up to 3 Weeksand observed for the production of litters. The day pregnancy occurred(DPO) is then back calculated from the day of parturition.

TAB LE III N o. Iitters/ DPO, No. rats Days mean Range treated eohabitedIt will be observed from the above data that the compounds of theinvention and especially those wherein R is caproyl or decanoyl exhibitactivity of long duration against reproduction. For example, for thecaproyl compound, wherein cohabitation existed for 91 days only one ratof 10 had a litter, the pregnancy for which occurred 70 days aftercohabitation began and 77 days after administration of the compound. Thedecanoyl compound is effective to suppress reproduction for an averageof 41 days after cohabitation in the rats tested While half the rats didnot become pregnant at all. These data show the long acting nature ofthe compounds in suppressing reproduction. Similar conclusions may bedrawn from the data on the acetyl and propionyl compounds. The rangefigure given indicates the earliest and latest days on which pregnancyoccurred.

In contrast to the results obtained from treated animals as described inTable III, it should be noted that results obtained over a long periodof time from rats permitted to cohabitate without the administration ofany anti-reproductive compounds show that of the female rats becamepregnant Within a range of 1-8 days after cohabitation with a mean DPOof four days.

What is claimed is:

1. A compound of the formula:

HON.

wherein R is alkanoyl of from 2 to 10 carbon atoms and R is methyl orethyl.

2. The compound of claim 1 wherein R is methyl. 3. The compound of claim2 wherein R is caproyl. 4. The compound of claim 2 wherein R is acetyl.5. The compound of claim 2 wherein R is propionyl. 6. The compound ofclaim 2 wherein R is decanoyl. 7. The compound of claim 1 wherein R isethyl. 8. The compound of claim 7 wherein R is acetyl.

References Cited UNITED STATES PATENTS 3,060,205 10/ 1962 Schwenk et a1260--397.5 3,211,756 10/1965 Mazur 260--397.1 3,299,107 l/1967 Mazur260397.5 3,374,230 3/1968 Gardner et a1. 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 424-238 kw UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION patent 3,780,073 Dated December18,1973

Inventor(s) Arvin I. Shroff It is certified that error appeafs in theabove-identified patent and that said Letters Patent are herebycorrected as shownbelow:

' OR In Column 1, Formula 1, should r d (H In Column 2, line 30,"175-caproyloxy" should read 17 ethynyl-l9-norandrost-)+ ..175 1-3 mimeIn Column 2, line m, "yrsro ion lox -n -eth n l" should read1'531-Caproyloxy-l7d -ethynyl In Column 2, lime 55, "lT-BedecanQyloXy-NQ-ethynyl" should read. 175-Propionyloxy-l7d-ethynyl In Column 3, lines13 and 1h, A solution containing 3.0g of l7e(,-ethynyl-l76 should beinserted before "acetoxy -l9-norandrost &- n-3-one".

In Column 6, Claim 1,

OR RI .c-z-cH OR should read C=;CH

HON

' HON (SEAL) Attest:

EDWARD ILI LETCIIER IR. C. I-L- ..SHALL .l-Jl-I Attosting OfficerCommissioner of Patents

